title: CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells.
abstract: A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G(1)/G(0) phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma.
authors.affiliation: Division of Tumor Genetics B030, Clinical Cooperation Unit Pediatric Oncology G340, German Cancer Research Center, Bioquant, Heidelberg, Germany. k.henrich@dkfz.de
authors.forename: Kai-Oliver
authors.initials: KO
authors.lastname: Henrich
authors.forename: Tobias
authors.initials: T
authors.lastname: Bauer
authors.forename: Johannes
authors.initials: J
authors.lastname: Schulte
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Hedwig
authors.initials: H
authors.lastname: Deubzer
authors.forename: Sina
authors.initials: S
authors.lastname: Gogolin
authors.forename: Daniel
authors.initials: D
authors.lastname: Muth
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.forename: Manfred
authors.initials: M
authors.lastname: Schwab
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002878:Chromosomes, Human, Pair 1; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C487554:CAMTA1 protein, human; D002135:Calcium-Binding Proteins; D015534:Trans-Activators